We propose to study the role of retinoic acid on events regulating tumor invasion and metastasis. This research will be done primarily in Argentina, at the Institute of Oncology "Anegel. H. Roffo", University of Buenos Aires, in collaboration with Rafael Mira-y-Lopez, Mount Sinai School of Medicine, as an extension of NCI grant CA-54273. Retinoic acid (RA), the chief bioactive metabolite of vitamin A, signals via RA receptors (RARs) and rexinoid receptors (RXR) to regulate diverse biological events essential for embryonic development and for organ homeostasis, cell growth, differentiation and death. Much evidence supports the notion that RA can interfere with oncogenesis, impairing tumor development and growth. However, the role of RA on the critical processes of tumor invasion and metastasis have not been systematically studied. Moreover, little is known about the role of myoepithelial cells, which interact closely with the ductal epithelial cells, on these key processes. Even less is known about the effects of RA on myoepithelial cells and its supporting role in transformation. A major goal of the parent grant is to define the role of physiological RA in mammary development and carcinogenesis but the parent grant does not address either invasion and metastasis or the role of myoepithelial cells. This collaborative proposal is meant to fill this gap. We will use a spontaneous murine mammary carcinoma model developed by the Foreign PI (LM38), which metastasizes to draining lymph nodes and lungs and contain both epithelial and myoepithelial cell components, and from which several sublines have been established. Our Specific Aims are to first characterize the ability of LM38 derivatives to biosynthesize RA and their expression of RARs and RXRs; second, to use receptor-selective retinoids to test the hypothesis that this class of agents modulate critical steps in the metastatic cascade (adhesion, migration, invasion, protease expression, etc); and third, to use genetically modified cells to specifically implicate distinct RAR and RXR species in the retinoid regulation of metastasis.